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1.
Front Immunol ; 12: 767099, 2021.
Article in English | MEDLINE | ID: mdl-34899718

ABSTRACT

B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor that is expressed by lymphoid cells and regulates the immune response. Consistent with an inhibitory role for BTLA, the disease is exacerbated in BTLA-deficient lupus mice. We recently demonstrated that the BTLA pathway is altered in CD4+ T cells from lupus patients. In the present work, we aimed at delineating the expression pattern of BTLA on CD4+ T cell subsets suspected to play a key role in lupus pathogenesis, such as circulating follicular helper T cells (cTFH) and regulatory T cells (Tregs). We did not detect significant ex vivo variations of BTLA expression on total CD4+ T cells (naive and memory), cTFH or TFH subsets between lupus patients and healthy controls. However, we interestingly observed that BTLA expression is significantly increased on activated Tregs, but not resting Tregs, from lupus patients, especially those displaying an active disease. Moreover, it correlates with the diminution of the Tregs frequency observed in these patients. We also showed that both BTLA mRNA and protein expression remain low after TCR stimulation of activated Tregs sorted from healthy donors and evidenced a similar dynamic of BTLA and HVEM expression profile by human Tregs and effector CD4+ T cells upon T cell activation than the one previously described in mice. Finally, we observed that the HVEM/BTLA ratio is significantly lower in Tregs from lupus patients compared to healthy controls, whereas ex vivo effector CD4+ T cells express higher BTLA levels. Our data suggest that an altered expression of BTLA and HVEM could be involved in an impaired regulation of autoreactive T cells in lupus. These results provide a better understanding of the BTLA involvement in lupus pathogenesis and confirm that BTLA should be considered as an interesting target for the development of new therapeutic strategies.


Subject(s)
Gene Expression Regulation/immunology , Lupus Erythematosus, Systemic/immunology , Receptors, Immunologic/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Adolescent , Adult , Aged , Aged, 80 and over , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , Female , Humans , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/metabolism , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Male , Middle Aged , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Receptors, Tumor Necrosis Factor, Member 14/genetics , Receptors, Tumor Necrosis Factor, Member 14/immunology , Receptors, Tumor Necrosis Factor, Member 14/metabolism , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism , Young Adult
2.
JCI Insight ; 3(13)2018 07 12.
Article in English | MEDLINE | ID: mdl-29997289

ABSTRACT

Coinhibitory receptors play an important role in the prevention of autoimmune diseases, such as systemic lupus erythematosus (SLE), by limiting T cell activation. B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, similar to cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1), that negatively regulates the immune response. The role of BTLA in the pathogenesis of autoimmune diseases in humans and, more specifically, in SLE is largely unknown. We investigated BTLA expression on various T cell subsets, and we did not observe significant variations of BTLA expression between lupus patients and healthy controls. However, the enhancement of BTLA expression after activation was significantly lower in SLE patients compared with that in healthy controls. Furthermore, we found an impaired capacity of BTLA to inhibit T cell activation in SLE due to a poor BTLA recruitment to the immunological synapse following T cell stimulation. Finally, we demonstrated that defective BTLA function can be corrected by restoring intracellular trafficking and by normalizing the lipid metabolism in lupus CD4+ T cells. Collectively, our results evidence that the BTLA signaling pathway is altered in SLE T cells and highlight the potential of targeting this pathway for the development of new therapeutic strategies in lupus.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Lipid Metabolism , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Receptors, Immunologic/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Autoimmune Diseases , CD4-Positive T-Lymphocytes/drug effects , CTLA-4 Antigen/metabolism , Cell Proliferation , Female , France , Humans , Lymphocyte Activation , Male , Middle Aged , Programmed Cell Death 1 Receptor/metabolism , Receptors, Immunologic/antagonists & inhibitors , Signal Transduction , Young Adult
3.
J Immunol Res ; 2016: 5767106, 2016.
Article in English | MEDLINE | ID: mdl-27635407

ABSTRACT

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyperactivity leading to the production of autoantibodies, some of which having a deleterious effect. Reducing autoantibody production thus represents a way of controlling lupus pathogenesis, and a better understanding of the molecular and cellular factors involved in the differentiation of B cells into plasma cells could allow identifying new therapeutic targets. Follicular helper T cells (TFH) represent a distinct subset of CD4(+) T cells specialized in providing help to B cells. They are required for the formation of germinal centers and the generation of long-lived serological memory and, as such, are suspected to play a central role in SLE. Recent advances in the field of TFH biology have allowed the identification of important molecular factors involved in TFH differentiation, regulation, and function. Interestingly, some of these TFH-related molecules have been described to be dysregulated in lupus patients. In the present review, we give an overview of the aberrant expression and/or function of such key players in lupus, and we highlight their potential as therapeutic targets.


Subject(s)
Germinal Center/cytology , Lupus Erythematosus, Systemic/therapy , T-Lymphocytes, Helper-Inducer/immunology , Adult , Autoantibodies/immunology , B-Lymphocytes/immunology , Cell Differentiation , Germinal Center/immunology , Humans , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/physiopathology , Molecular Targeted Therapy , Plasma Cells/immunology , T-Lymphocytes, Helper-Inducer/metabolism
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